Scleroderma, Systemic
Conditions
Keywords
Systemic Sclerosis, Anti-CD19 CAR T-cells, Autologous CAR T-cell therapy
Brief summary
The goal of this clinical trial is to evaluate whether anti-CD19 CAR T-cell therapy can improve disease activity in adults with severe, treatment-resistant systemic sclerosis (SSc). The study will also assess the safety of this therapy and how CAR T-cells behave in the body. The main questions are: Does CAR T-cell therapy reduce skin thickening and other signs of SSc? What side effects occur after receiving CAR T-cells? How do CAR T-cells expand, persist, and affect B-cells and autoantibodies? Participants will: Undergo leukapheresis Receive short lymphodepleting chemotherapy Receive one infusion of anti-CD19 CAR T-cells Stay in the hospital for about 10 days Attend follow-up visits for 24 months with clinical exams, blood tests, and organ-function assessments Optional skin or lymph-node biopsies may be performed in participants who consent to these procedures. This study aims to provide early evidence on whether CAR T-cell therapy could become a promising treatment option for systemic sclerosis.
Detailed description
Systemic sclerosis (SSc) is a rare and severe autoimmune disease characterized by fibrosis of the skin and multiple organs, vasculopathy, and immune dysregulation. Many patients continue to experience active and progressive disease despite conventional immunosuppressive treatments, including disease modifying antirheumatic drugs (DMARDs) and biologics. Therapeutic options remain limited, and there is a significant unmet medical need for innovative approaches targeting the underlying mechanisms of the disease. Recent preliminary experience from studies conducted in autoimmune diseases-such as lupus, myositis, and systemic sclerosis-suggests that autologous anti CD19 CAR T cell therapy may help reduce disease activity. Reported observations include transient B cell depletion, decreases in autoantibody levels, and improvements in joint, pulmonary, and cardiac manifestations. These early results support further evaluation of CAR T cell therapy in systemic sclerosis in a structured clinical trial setting. This Phase IIa, multicenter, single-arm study is designed to evaluate the feasibility and safety of autologous anti-CD19 CAR-T cell therapy in adults with active systemic sclerosis who are resistant to immunosuppressive treatments. The study also aims to generate early clinical and biological data to assess the potential value of this therapeutic strategy in this population. Eligible participants will undergo leukapheresis for T-cell collection. Following standard manufacturing of autologous anti-CD19 CAR-T cells in a GMP (Good Manufacturing Practice)-certified facility, participants will receive a short course of lymphodepleting chemotherapy, followed by a single intravenous infusion of CAR-T cells. They will remain hospitalized for intensive monitoring during the early post-infusion period, in accordance with established procedures for CAR-T cell therapies. Participants with known hypersensitivity to drugs required for treatment-related toxicity are excluded, as specified in the protocol. After discharge from the hospital, participants will have follow-up visits for up to 24 months. These visits will include clinical and biological assessments as well as appropriate imaging tests to monitor disease activity, treatment safety, and overall health status. Biological samples will also be collected at specific times for centralized analysis. The study incorporates exploratory immunological and translational research components. These may include monitoring circulating CAR T cells, characterizing immune cell subsets, and evaluating selected biomarkers. Optional skin and lymph node biopsies may be performed in consenting participants to analyze immune cell phenotypes and tissue level changes associated with treatment. Additional exploratory analyses may assess the spatial organization and distribution of immune cells within tissue samples, as described in the study protocol. Overall, the study aims to provide early data on the use of anti CD19 CAR T cell therapy in systemic sclerosis, including feasibility, safety, and biological signals of activity. The results are expected to contribute to the development of innovative cell based therapeutic strategies for this severe autoimmune disease.
Interventions
BIOLOGICALCD19 CAR T Arm
Autologous anti-CD19 CAR-T cells are generated from the participant's leukapheresis product in a Good Manufacturing Practice (GMP)-certified facility using a lentiviral vector. Prior to infusion, participants will receive a short course of lymphodepleting chemotherapy. A single intravenous infusion of autologous anti-CD19 CAR-T cells will be administered on Day 0 at a target dose of 1 × 10⁶ CAR-T cells/kg. Participants will then be monitored in the hospital in accordance with standard post-CAR-T cell infusion procedures.
Sponsors
University Hospital, Montpellier
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A phase 2a, multicenter, open-label, single-arm study to investigate the efficacy of anti-CD19 CAR T-cell therapy in patients with systemic sclerosis who are resistant to immunosuppressive therapy
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
Pre-Inclusion criteria: 1. Diagnosis of systemic sclerosis according to ACR/EULAR 2013 classification (15).we include in the critera the fulfilling of 2013 EULAR/ACR criteria and specify disease duration (less than 2 years), score/clinical evidence for active disease : 2. Severe and resistant to low dose steroids and at least 2 immunosuppressive treatment including csDMARDs (methotrexate, azathioprine, mycophenolate mofetil) and at least one bDMARDs (Tocilizumab) 3. Early onset (less than 2 years). 4. Severity \& progression of disease be defined by : 1. .mRSS \>15 with at least one organ involvement (lung: FVC \<80%, renal involvement, cardiac involvement, Creatinine \< 1.5 mg/dl within 6 months). 2. mRSS \<15 and lung fibrosis progression (FVC -10% DLCO -15% within 6 months) 5. patients with active disease (as defined by EUSTAR ≥2.5) and to patients with a worsening disease despite 6 months of at least 2 immunosuppressive treatments including one DMARDs (methotrexate, azathioprine, mycophenolate mofetil), and one biological DMARD rituximab or tocilizumab. 6. Estimated survival time \> 24 weeks 7. Age: ≥18 ≤64 years old voluntary to participate in the study and sign the informed consent 8. Adequate organ functions assessed : 1. serum Creatinine clearance \> 40ml/mi 2. adequate bone marrow function (Hemoglobin ≥9g/dL ; PMN ≥ 1 G/L ; Platelets ≥ 100 G/L) 3. Alanine aminotransferase (ALT) ≤ 3 x ULN and total bilirubin \< 2.0 mg/dL (34 μmol/L) (or \< 3.0 mg/dL \[51 μmol/L\] for subjects with Gilbert's syndrome) 4. Adequate respiratory function: no dyspnea or grade I dyspnea (Common Terminology Criteria for Adverse Events (NCI CTCAE v 5.0) and oxygen saturation \>/= 92% on room air 9. Highly effective contraception methods Inclusion criteria: 1. Adequate organ functions assessed: 1. serum Creatinine clearance \> 40ml/mi 2. adequate bone marrow function (Hemoglobin ≥9g/dL ; PMN ≥ 1 G/L ; Platelets ≥ 100 G/L) 3. Alanine aminotransferase (ALT) ≤ 3 x ULN and total bilirubin \< 2.0 mg/dL (34 μmol/L) (or \< 3.0 mg/dL \[51 μmol/L\] for subjects with Gilbert's syndrome) 4. Adequate respiratory function: no dyspnea or grade I dyspnea (Common Terminology Criteria for Adverse Events (NCI CTCAE v 5.0) and oxygen saturation \>/= 92% on room air 2. Adequate venous access for apheresis 3. Leucapheresis : a wash-out period of 6 weeks for conventional immunosuppressants (i.e. methotrexate, mycophenolate mofetil) 4. Leucapheresis : at least 12 weeks after biotherapy (i.e. tocilizumab, 6 months for rituximab),
Exclusion criteria
1. Craniocerebral trauma, conscious disturbance, epilepsy, cerebrovascular ischemia or cerebrovascular hemorrhagic diseases 2. ECG showing prolonged QT interval or history of severe heart diseases or FEVG \< 40% 3. Lung and / or heart severe dysfunction defined by CVF\<50% and/or DLCO \<40% 4. Pulmonary arterial hypertension defined by catheterism (mean AP \> 25mmHg at rest or \> 30mmHg after exercise, PAOP \< 15mmHG) 5. Clinically significant active, opportunistic, chronic or recurrent infection (including but not limited to: hepatitis B or C virus or HIV) or covid-19 \< 1 months including active or latent tuberculosis (TB) infection 6. Contra indication for autologous hematopoietic stem cell transplantation (AHSCT ) or relapsing at least one year after AHSCT 7. Active hematological or solid neoplasm 8. Concurrent therapy with systemic steroids (\>10 mg/d prednisone equivalent) within 2 weeks prior to inclusion, except inhaled steroids 9. Methylprednisolone or prednisone (maximum dose 20 mg) instead of immunosuppressive agents 10. T cell targeting drugs (e.g. mycophenolate mofetil, azathioprine, calcineurin inhibitors) within 6 weeks prior to leukapheresis 11. Previous adoptive T cell therapy or any gene therapy including CAR T cell therapy 12. Live vaccines within 6 weeks prior to leukapheresis 13. Hypersensitivity against any drug or its ingredients/impurities that is scheduled or likely to be given during trial participation, e.g. as part of the mandatory preparative chemotherapy or rescue medication/salvage therapies for treatment related toxicities 14. patients without social security coverage; 15. patients under guardianship; 16. Male or female patients seeking to conceive a child 17. Women of childbearing potential unless they are using a highly effective method of contraception starting from the time of enrolment and for at least 12 months following LD chemotherapy and until clearance of CAR-T cells, and sexually active male participants unwilling to use a condom. Female partners of sexually active male participants must be on a highly effective form of birth control from the time of enrolment and for at least 12 months following LD chemotherapy and until clearance of CAR-T cells. 18. pregnant or breastfeeding women; 19. patients with advanced cognitive disorders or any other cause preventing their informed consent; 20. active, clinically significant CNS pathology : If signs or symptoms exist which present diagnostic uncertainty, neurologist consultation will be obtained to confirm the diagnosis of any neurological condition 21. any comorbidity, whatever it may be, which may, in the opinion of the investigator, place the patient at additional risk or interfere with the monitoring of the study. 22. Concurrent participation in any other interventional trial and Contraindication to the lymphodepleting chemotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| modified Rodnan skin score (mRSS) | 6 Months | Clinical response will be assessed through the modified Rodnan skin score (mRSS) which measures skin thickness on a scale of 0 to 3 at 17 anatomical sites (score range 0-51, higher scores indicating worse skin fibrosis) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in European Scleroderma Trial And Research (EUSTAR) activity index | From 3 months to 1 month before CAR-T cell infusion | Clinical response will also be assessed through the European Scleroderma Trial And Research (EUSTAR) disease activity (range 0-10, higher scores indicating greater disease activity) based on a weighted 10-point activity index : Δ-skin=1.5 (Δ=patient assessed worsening during the previous month), modified Rodnan skin score (mRss) \>18=1.5, digital ulcers=1.5, tendon friction rubs=2.25, C-reactive protein \>1 mg/dL=2.25 and diffusing capacity of the lung for CO (DLCO) % predicted \<70%=1.0. A cut-off ≥2.5 was found to identify patients with active disease |
| modified Rodnan skin score (mRSS) | From 3 months to 1 month before CAR-T infusion | Clinical response will be assessed through the modified Rodnan skin score (mRSS) which measures skin thickness on a scale of 0 to 3 at 17 anatomical sites (score range 0-51, higher scores indicating worse skin fibrosis) |
| Change in Revised Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (rCRISS) | From 3 months to 1 month before CAR-T infusion | Clinical response will be assessed using the revised Combined Response Index in diffuse cutaneous Systemic Sclerosis (rCRISS). The rCRISS is a 2-step composite score: Step 1: Patients are considered not improved if any of the following occur: scleroderma renal crisis, significant FVC decline (≥15% or FVC% \<80%), new left ventricular failure (LVEF ≤45%), new pulmonary arterial hypertension requiring treatment, gastrointestinal dysmotility requiring nutritional support, or digital ischemia requiring treatment or hospitalization. Step 2: For other patients, improvement is defined as ≥40% improvement in at least 3 of 5 measures: mRSS, HAQ-DI, patient global assessment, clinician global assessment, and percent predicted FVC. Additional assessments include spirometry (FVC, DLCO), thoracic CT fibrosis, echocardiography (LVEF, global longitudinal strain), cardiac MRI, and SHAQ score |
| Change in the lung capacity FVC (forced vital capacity) | From 3 months to 1 month before CAR-T infusion | To assess the impact of the treatment on pulmonary function, FVC will be assessed during functionnal exploration test lab and we will evaluate the improvement in FVC over time |
| Change in DLCO (diffusing capacity of the lung for carbon monoxide) | From 3 months to 1 month before CAR-T infusion | The efficacy of the treatment on pulmonary function will also be analyzed by monitoring changes in DLCO (diffusing capacity of the lung for carbon monoxide), quantifiy during functionnal exploration test lab |
| Extent of fibrosis on pulmonary CT (Computed Tomography) | From 3 months to 1 month before CAR-T infusion | Pulmonary response will be also assessment by CT scan and expressed as percentage of parenchyma affected. The type of parenchymal involvement willbe specified (ground glass, honeycomb) |
| Extent of fibrosis on pulmonary CT(Computed Tomography) | 3 Months | Pulmonary response will be also assessment by CT scan and expressed as percentage of parenchyma affected. The type of parenchymal involvement willbe specified (ground glass, honeycomb) |
| Change in cardiac ejection fraction and global longitudinal strain | From 3 months to 1 month before CAR-T infusion | A transthoracic cardiac ultrasound will be performed regularly to assess the effect of treatment on the left ventricular ejection fraction, as well as the global longitudinal strain (GLS). |
| Cardiomyopathy, change in cardiac MRI (Magnetic Resonance Imaging) signal | From 3 months to 1 month before CAR-T infusion | A cardiac MRI (Magnetic Resonance Imaging) will be performed at baseline and at follow-up visit to evaluate the effect of treatment on T1 and T2 mapping, late gadolinium enhancement (LGE), extracellular volume ( ECV) mapping and indirect indicators of pulmonary hypertension |
| Change in scleroderma-adapted Scleroderma Health Assessment Questionnaire (SHAQ) score | Day 0 (CAR-T infusion) | Clinical response will be assessed using SHAQ : the patient will complete a self-assessment questionnaire on their health status during systemic sclerosis (SSc) and we will compare the scores at each stage |
| Change in Health Assessment Questionnaire Disability Index HAQ-DI score | Day 0 (CAR-T cell infusion) | The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a quantitative tool used to measure health related quality of life assessments related to SSc ; Clinical response will be assessed using HAQ-DI and we will compare the scores at each stage |
| Change in Health Assessment Questionnaire Cochin Hand score | Day 0 (CAR-T cell infusion) | Clinical response will also be assessed using the Cochin Hand Function Scale, a validated tool that quantifies disability resulting from hand functional impairment. |
| Change in quality of life Questionnaire SF-36 | Day 0 (CAR-T cell infusion) | Clinical response will also be assessed using the SF36 score collected at each time point through the SF36 self-assessment questionnaire, which evaluates the patient's quality of life across eight domains, including physical functioning, role limitations, bodily pain, general health, vitality, social functioning, emotional well-being, and mental health |
| Change in the university of California Los Angeles scleroderma clinical trials consortium gastrointestinal tract (ULCA-SCTC GIT) score | Day 0 (CAR-T cell infusion) | to evaluate disease response on to systemic sclerosis associated gastrointestinal tract symptoms severity and its impact on patients' well-being, we will compare ULCA-SCTC GIT Score, which is a self-administered questionnaire completed at each time point |
| Change in Malnutrition Universal Screening Tool (MUST) score | From 3 months to 1 month before CAR-T cell infusion | We will also assess the effect of treatment on digestive impairment in scleroderma patient, as well as their risk of malnutrition, using the MUST score. This evaluation includes measuring the percentage of weight loss over the previous 3 to 6 months, calculating body mass index, and determining whether the patient has been seriously ill and experienced a period of more than 5 days without nutritional intake |
| Anti-antibody titers | From 3 months to 1 month before CAR-T cell infusion | Measurement of antinuclear antibodies (ANA), anti-centromere, anti-DNA, anti-Topoisomerase, and TRAK antibody titers following CAR T anti-CD19 cell administration |
| CAR T cell counts | Day 0 (CAR-T cell infusion) | Quantification of CAR T cells using flow cytometry and qPCR to assess expansion and persistence after CAR T anti-CD19 infusion |
| Immunophenotyping of B, T, and NK cells subsets | Day -14 (14 days before CAR-T infusion) | Immunophenotyping of B cells, T cells, NK cells, and immune subpopulations to evaluate immune reconstitution following CAR T infusion |
| B-cell receptor (BCR) repertoire analysis | Day -14 (14 days before CAR-T infusion) | BCR repertoire analysis performed on B cells from Systemic Sclerosis (SSc) patients. Assessment occurs at Month 6 if B-cell percentage is \>50% of baseline; otherwise at Month 12 after CAR T anti-CD19 administration |
| Skin biopsies for single-cell phenotyping | From 3 months to 1 month before CAR-T infusion | Skin biopsies (for patients who have given their consent) performed at baseline for single-cell phenotyping analyses. |
| lymph node biopsies for single-cell phenotyping | 3 Months | lymph node biopsies (for patients who have given their consent) performed at Month 3 for single-cell phenotyping analyses. |
| Incidence rate of adverse events | Day -14 to 24 months | Incidence rate of adverse events graded according to the Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 and classified following the American Society of Clinical Oncology (ASCO) guidelines |
| Incidence of Cytokine Release Syndrome (CRS) | Day -14 to 24 months | Incidence and severity of Cytokine Release Syndrome (CRS), graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system. |
| Incidence of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) | Day -14 to 24 months | Incidence and severity of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system |
| Incidence of Cytopenias | Day -14 to 24 months | Incidence and severity of cytopenias, graded according to the consensus grading system of the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT) consensus grading system |
| Incidence of Infections | Day -14 to 24 months | Incidence and severity of infections, graded according to Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. |
| Incidence of Cardiac Events | Day -14 to 24 months | Incidence and severity of cardiac adverse events, graded according to Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. |
| Incidence of Acute Kidney Injury | Day -14 to 24 months | Incidence and severity of acute kidney injury, graded according to Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. |
| Incidence of Scleroderma Renal Crisis | Day -14 to 24 months | Incidence of clinically diagnosed scleroderma renal crisis |
Countries
France
Contacts
PRINCIPAL_INVESTIGATORChristian Jorgensen, PUPH
University Hospital, Montpellier
Outcome results
None listed